Stable pharmaceutical compositions of succinylcholine chloride

ABSTRACT

The present invention relates to injectable pharmaceutical compositions comprising therapeutically effective amount of succinylcholine chloride, one or more pharmaceutically acceptable aqueous solvents, and one or more stabilizing agents selected from aliphatic polyols; lower alkyl alcohols; amino acids having at least one additional amino, carboxyl or hydroxyl group; amino alcohols; and aliphatic dicarboxylic acids having at least one hydroxyl or amino group, or α-β unsaturation. The compositions are stable at room temperature for at least 30 days. Methods of manufacturing the injectable pharmaceutical compositions are also provided. The composition may be provided in a sealed container, e.g., an ampoule, vial and pre-filled syringe, and are suitable for subcutaneous, intravenous or intramuscular administration as an adjunct to general anesthesia, to facilitate tracheal intubation, and/or to provide skeletal muscle relaxation during surgery or mechanical ventilation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian Patent Application No.202141038846 filed Aug. 27, 2021, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to stable injectable pharmaceuticalcompositions of succinylcholine chloride or pharmaceutically acceptablesolvates, or hydrates thereof and methods for manufacturing the same.The composition may be provided in a sealed container, e.g., an ampoule,vial and pre-filled syringe, and are suitable for subcutaneous,intravenous or intramuscular administration.

BACKGROUND OF THE INVENTION

Succinylcholine chloride is a di-quaternary base consisting of thedichloride salt of the dicholine ester of succinic acid. Succinylcholineis a short-acting, depolarizing-type, skeletal muscle relaxant.Succinylcholine has long been the favoured neuromuscular blocking agentand drug of choice for emergent airway management because of its rapidonset, dependable effect, and short duration. Succinylcholine combineswith the cholinergic receptors of the motor end plate to producedepolarization. This depolarization may be observed as fasciculations.Subsequent neuromuscular transmission is inhibited so long as adequateconcentration of succinylcholine remains at the receptor site. Onset offlaccid paralysis is rapid (less than one minute after intravenousadministration), and single administration lasts approximately 4 to 6minutes. The chemical name of succinylcholine chloride is2,2′-[(1,4-dioxo-1,4-butanediyl)bis(oxy)]bis[N,N,Ntrimethylethanaminium]dichloride and its chemical structure is represented by the structuralFormula (I).

Succinylcholine chloride is freely soluble in water, slightly soluble inalcohol and practically insoluble in ether. Succinylcholine chloride hasbeen approved as an adjunct to general anaesthesia, to facilitatetracheal intubation, and to provide skeletal muscle relaxation duringsurgery or mechanical ventilation.

Succinylcholine chloride is currently approved and marketed in theUnited States under the brand names ANECTIN® and QUELICIN®. For shortsurgical procedures in adults, recommended optimum dose varies amongindividuals and may be from 0.3 to 1.1 mg/kg succinylcholine injectiongiven intravenously to produce neuromuscular blockade and to facilitatetracheal intubation. For long surgical procedures, the dose ofsuccinylcholine administered by infusion, after diluting toconcentration from 1 mg/mL to 2 mg/mL, depends upon the duration of thesurgical procedure and the need for muscle relaxation. The average rateof infusion for an adult range between 2.5 and 4.3 mg per minute.

Succinylcholine chloride may be present in ionized form in aqueoussolution practically all over the ranges of pH because of the presenceof a quaternary ammonium salt. Since the hydrolytic cleavage of ordinaryesters is catalysed by hydrogen and/or hydroxyl ions, it is consideredthat the ester-linkages in succinylcholine chloride might also besubject to hydrogen or hydroxyl ion catalysing reaction.

The hydrolysis of succinylcholine is catalyzed by both hydrogen ions andhydroxyl ions. Succinylcholine in aqueous solution hydrolyzes rapidly toform an inactive monoester (succinylmonocholine), which subsequentlyundergoes much slower hydrolysis to yield choline and succinic acid.During the degradation of succinylcholine, production of succinic aciddecreases the pH value and speeds up the hydrolysis reaction. Finally,the rate of hydrolysis remains constant because of the slow down effectof the decreased succinylcholine concentration (Adnet et al., Emerg MedJ 2007; 24:168-169).

Succinylcholine solutions are often kept at room temperature inemergency resuscitation carts, because of the need for immediateavailability in emergency room settings. This presents a challengebecause succinylcholine decomposes at a considerably higher rate whenthe temperature is elevated. Injectable formulations containingsuccinylcholine chloride are very challenging to manufacture since theydegrade rapidly at elevated temperatures. In order to compensate for theloss of succinylcholine at elevated temperatures, it is a commonpractice to add overages while manufacturing the composition.

All commercially available injections of succinylcholine chloride arestored at 2° C. to 8° C. Commercial Succinylcholine chloride injectionsin the original unopened containers are stable for 14 days at roomtemperature.

International publication no. WO2022018177A1 (“Aguettant”) seeks toameliorate a need to dilute commercial solutions of succinylcholinechloride (having concentrations of 20-50 mg/ml), which is associatedwith risks of medical errors, contamination concerns and reduced shelflife of diluted solutions. Aguettant is said to provide ready to useaqueous solution of succinylcholine chloride having a concentration of10 mg/ml buffered at a pH ranging from 3.0 to 4.5 with succinic acid, ata concentration ranging from 5 mM to 20 mM, having stability at 2-8° C.of up to 24 months and at room temperature for up to 3 months. Aguettantasserts that the selection of the specified concentration of succinicacid in the composition was essential for avoiding pH modificationduring the shelf life and ensure stability as it provides sufficientbuffering without increase in degradation kinetics of succinylcholine,triggered by lower pH inherent with high concentrations of succinicacid. The publication also provides a preferred process of steamsterilization at 121° C. of the composition wherein succinylcholinechloride overages of 5% are used to compensate for degradation duringthe manufacturing and storage of the composition. However, the onlyexample of the claimed composition that show stability of thecomposition at room temperature for several months combine the specifiedsuccinic acid concentration, pH range, and steam sterilization.

When succinylcholine injection is placed along with other potent drugsused in emergency room settings, accidental mix-up and administration ofunintended drug may occur. There is an imminent risk of death due tomedication errors. Accidental administration of succinylcholine may leadto respiratory arrest and death. It is very important to confirm properselection of intended drug and avoid confusion with other injectablesolutions that are present in critical care and other clinical settings.

The factors described above influence the safety, quality & efficacy offinished product comprising succinylcholine. Because of the problemsassociated with manufacture, storage and manner of use ofsuccinylcholine described above and the limitations with currentlyavailable products of succinylcholine chloride, it is desirable todevelop a stable injectable succinylcholine chloride solution for humanuse, which is safe, therapeutically effective, easy to differentiatefrom look-a-like injections, ready to dilute or ready to administer, andhas prolonged room temperature stability without any significant loss ofpotency.

The present invention fulfils this need by developing stable injectablesolutions of succinylcholine chloride and providing methods of efficientand safer use to achieve an improved standard of patient care.

SUMMARY OF THE INVENTION

The present invention relates to stable injectable solutions ofsuccinylcholine chloride, suitable for human use, with prolonged roomtemperature stability compared to the currently approved and marketeddosage forms of succinylcholine chloride and without any significantloss of potency.

The injectable pharmaceutical composition of the present inventioncomprises:

-   -   (i) therapeutically effective amount of succinylcholine        chloride;    -   (ii) one or more stabilizing agents;    -   (iii) one or more pharmaceutically acceptable solvents,

wherein the composition is stable at room temperature for at least 30days,

wherein water is at least one of the pharmaceutically acceptablesolvents, and

wherein the stabilizing agents are selected from the group consisting ofaliphatic polyols; lower alkyl alcohols; amino acids having at least oneadditional amino, carboxyl or hydroxyl group; amino alcohols; andaliphatic dicarboxylic acids having at least one hydroxyl or aminogroup, or α-β unsaturation.

In one aspect of the invention, the injectable pharmaceuticalcomposition is free of tonicity contributing agent.

In another aspect, the injectable pharmaceutical composition has totalimpurities of less than about 6.0% (w/w) as measured by HPLC, whenstored at 25° C./40% RH for up to 90 days.

In yet another aspect, the i injectable pharmaceutical composition hassuccinic acid impurity of less than about 0.5% (w/w) as measured byHPLC, when stored at 25° C./40% RH for up to 90 days.

In yet other aspects, the injectable pharmaceutical composition hassuccinylmonocholine impurity of less than about 5.0% (w/w) as measuredby HPLC, when stored at 25° C./40% RH for up to 90 days.

In other aspects, the injectable pharmaceutical composition has cholineimpurity of less than about 3.0% (w/w) as measured by HPLC, when storedat 25° C./40% RH for up to 90 days.

The inventive injectable pharmaceutical composition may be sterilizedusing a technique selected from the group consisting of filtrationthrough aseptic filtration-filling-sealing process, terminalsterilization, incorporation of sterilizing agents, irradiation, andheating.

In another aspect, the injectable pharmaceutical composition is disposedin a pre-filled syringe or vial.

In yet another aspect, the invention provides a kit comprising aninjection device for administration of the injectable pharmaceuticalcomposition to a subject in need of such pharmaceutical composition,wherein the injection device comprises a needle and prefilled syringe orsyringe cartridge with the composition disposed therein.

In another aspect, the injectable pharmaceutical composition furthercomprises one or more pharmaceutically acceptable excipients selectedfrom the group consisting of buffering agents, pH adjusting agents,tonicity contributing agents, antioxidants, chelating agents andpreservatives.

In a further aspect, the injectable pharmaceutical composition uponintravenous or intramuscular administration exhibits bioequivalence to acommercially available reference succinylcholine chloride drug products(such as ANECTIN® and QUELICIN®), and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for meanAUC0-t between about 80% and about 125%; (ii) a confidence interval formean AUC0-infinity between about 80% and about 125%; (iii) a confidenceinterval for mean Cmax between about 80% and about 125% or a combinationthereof.

In certain aspects, the invention relates to methods for making theinjectable pharmaceutical composition, which comprise: (i) dispensing80% v/v water for injection; (ii) sequentially adding stabilizing agentand stirring to form solution-1; (iii) adding succinylcholine chlorideto solution-1 and stirring to form solution-2; (iv) adjusting the pH ofthe solution-2 by adding a suitable pH adjusting agent; (v) making upthe final volume with remaining water for injection to obtain finalsolution; (vi) purging nitrogen gas throughout the procedure; (vii)filtering the final solution; (viii) filling the solution in pre-filledsyringes or vials and stoppering with coated stoppers.

In another aspect, the present invention relates to methods of treatmentcomprising administration of the injectable pharmaceutical compositionsof the invention to a subject in need thereof, as an adjunct to generalanesthesia, to facilitate tracheal intubation, and/or to provideskeletal muscle relaxation during surgery or mechanical ventilation.

The inventive pharmaceutical compositions are suitable for parenteraladministration via subcutaneous, intravenous or intramuscular routes andare provided in the form of aqueous solution.

The inventive injectable pharmaceutical compositions are advantageouslyready-to-use (RTU) or ready-to-dilute (RTD). An aspect of the inventionrelates to stable ready-to-use or ready-to-dilute succinylcholinechloride compositions suitable for parenteral administration.

In some embodiments, the succinylcholine chloride is present in theinjectable pharmaceutical composition at a concentration of about 5mg/mL to about 60 mg/mL, such as about 20 mg/mL.

In some embodiments, the injectable pharmaceutical composition hasosmolality value of between about 100 mOsm and about 2000 mOsm.

In other embodiments, the injectable pharmaceutical composition has a pHin the range of from about 3 to about 5.

In some embodiments, the stabilizing agent is selected from the groupconsisting of propylene glycol, polyethylene glycol, glycerol,cyclodextrin, cyclodextrin derivatives, ethanol, glutamic acid, asparticacid, arginine, lysine, meglumine, diethanolamine, tromethamine, maleicacid, tartaric acid, and mixtures thereof.

In some embodiments, the injectable pharmaceutical composition comprisesaliphatic polyols and/or lower alkyl alcohols as stabilizers at aconcentration of less than about 300 mg/mL.

In some embodiments, the injectable pharmaceutical composition comprisesstabilizers selected from the group consisting of amino acids having atleast one additional amino, carboxyl or hydroxyl group; amino alcohols;aliphatic dicarboxylic acids having at least one hydroxyl or aminogroup, or α-β unsaturation; and mixtures thereof at a concentration ofless than about 2 mg/mL.

In some embodiments, the pre-filled syringe is made up of a polymericmaterials selected from the group consisting of polysulfone,polycarbonate, polypropylene, polyethylene, ethylene/propylenecopolymers, polyolefins, acrylic-imide copolymers, polyester, poly(1,1,2,2 tetrafluoroethylene), Nylon, polyoxymethylene,polymethylpentene, polyvinylidene chloride, ethylvinylacetate, cyclicolefin polymer, cyclic olefin copolymer, crystal zenith, and mixturesthereof.

In one embodiment, the inventive injectable pharmaceutical compositioncomprises succinylcholine chloride at a concentration of about 20 mg/mL,propylene glycol, purified water, wherein the composition is free ofsodium chloride, wherein the composition is disposed in a pre-filledsyringe and is stable at room temperature for at least 30 days.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In case there are a plurality of definitions for the termsherein, the definitions provided herein will prevail.

As used herein, the term “room temperature” means a temperature of from59° F. to 77° F. (15° to 25° C.) that is suitable for human occupancyand at which laboratory experiments are usually performed.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. As used herein, the term “or” is generallyemployed in its usual sense including “and/or” unless the contentclearly dictates otherwise.

As used herein the term “succinylcholine” refers to succinylcholine freebase or a pharmaceutically acceptable salt, solvate or hydrate thereof.

As used herein, the term “about” means having a value falling within anaccepted standard of error of the mean when considered by one ofordinary skill in the art. Frequently, the term “about” refers to ±20%,preferably ±10%, and more preferably ±5% of the value or range to whichit refers.

Within the context of the present invention, the term “ready-to-use” or“RTU” as used herein refers to an injectable composition that is stableand is not reconstituted from a lyophilizate. The term “ready-to-use” or“RTU” also encompasses within its scope, injectable compositions thatare stable and do not require any reconstitution or dilution withparenterally acceptable diluent and can be directly administered to thepatient.

Within the context of the present invention, the term “ready-to-dilute”or “RTD” as used herein refers to an injectable composition that isstable and is diluted with a suitable diluent for parenteraladministration.

The terms “composition”, “pharmaceutical composition”, “pharmaceuticalproduct”, “dosage form”, “pharmaceutical dosage form”, “formulation”,“pharmaceutical formulation”, etc., refer to a pharmaceuticalcomposition that may be administered to a patient in need of treatment,which may be in any conventional formulation. For example, the term“pharmaceutical composition” as used herein refers to a solution forparenteral administration.

Within the context of this invention, the term “solution” refers to amixture of one or more substances dispersed molecularly (i.e.,dissolved) in a dissolving liquid medium or vehicle. The solution ispreferably homogeneous, in the sense that the active pharmaceuticalingredient (API) is essentially uniformly distributed and concentratedin the solution. The liquid solution may be viscous or not. A solutiondiffers from a suspension which comprises solid particles dispersedthroughout a liquid phase in which they are not soluble. As used herein,the term “solution” further means a solution which does not contain anyvisible particulate matter, solid particle, liposome or nanoparticles.The solution provides % transmittance, when measured at 650 nm, of notless than 90%, not less than 95%, not less than 98%, not less than 99%,not less than 99.5%, not less than 99.7% or not less than 99.8%.

The terms “parenterally acceptable liquid vehicle”, “vehicle”,“solvent”, “pharmaceutically acceptable solvent” and “parenterallyacceptable liquid solvent” are interchangeable.

The term “pharmaceutically acceptable excipient” as used herein means adiluent, carrier, or composition auxiliary, which is non-toxic andinert, which does not have undesirable effects on a subject to whom itis administered and is suitable for delivering a therapeutically activeagent to the target site without affecting the therapeutic activity ofthe active agent.

The terms “degradation product” or “impurity,” as used herein, refer tounwanted chemical products (including, but not limited to known orunknown related substances) that can develop during the manufacturing,transportation, and/or storage of drug products and can affect theefficacy of pharmaceutical products. These products can form in responseto changes in light, temperature, pH, and humidity, or due to inherentcharacteristics of active ingredient, such as their reaction withexcipients or on contact with the packaging.

The term “parenteral” or “injectable” refers to routes selected fromsubcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal(ID), intraperitoneal (IP) and the like.

The expression “bioequivalent” or “bioequivalence” is a term of art andis intended to be defined in accordance with Approved Drug Products withTherapeutic Equivalence Evaluations, 41^(th) Edition, which is publishedby the U.S. Department of Health and Human Services, and is commonlyknown as the “Orange Book”. Generally, bioequivalence can be defined asthe absence of significant difference in the rate and extent to whichthe active ingredient or active moiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drug actionwhen administered at the same molar dose under similar conditions in anappropriately designed study. Bioequivalence of different formulationsof the same drug substance involves equivalence with respect to the rateand extent of drug absorption. The pharmacokinetic characteristics ofthe concentration-time curve, such as the maximum observed plasmaconcentration (C_(max)), the time to reach C_(max), and the area underthe plasma concentration versus time curve (AUC), are examined bystatistical procedures which are well-established in the field ofpharmacokinetics. Two formulations whose rate and extent of absorptiondiffer by −20%425% or less are generally considered to be bioequivalent.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

The term “subject” refers to an animal, including a human or non-human.The terms patient and subject may be used interchangeably herein.Non-human may be a rat, a dog, a mouse or a guinea pig.

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The term “peak plasma drug concentration (Cmax)” means the maximumplasma drug concentration attained after drug administration.

The term “AUC_(0-infinity)” means the area under a plasma drugconcentration time curve from time point of 0 to infinity after drugadministration.

The term “AUC0-t” means the area under a plasma drug concentration-timecurve from time point of 0 to t after drug administration, wherein t istime in hours and is in between 1 hour to 72 hours.

As used herein, the term “storage” refers to the holding of acomposition under controlled or uncontrolled conditions for a periodranging from a few minutes to several months or longer. Storageconditions that can be controlled include, for example, temperature,humidity, and the level of light. In many cases, storage of apharmaceutical formulation is under industry acceptable standards and/orstandards that are mandated by regulatory agencies, such as USFDA.

By “therapeutically effective” amount is meant the amount of a drugsufficient to treat, prevent, or ameliorate a condition in a subject orpatient. The effective amount of succinylcholine chloride, used topractice the present invention for therapeutic management of a conditionmay be determined and adjusted by a person of ordinary skill to providethe appropriate amount and dosage regimen, e.g., depending upon one ormore of the manners of administration, the age, body weight, sex, and/orgeneral health of the patient.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

As used herein, “prolonged duration” refers to the holding of acomposition under controlled or uncontrolled conditions for a period ofmore than 21 days.

As used herein, “significant loss of potency” means that no more thanabout a 10% loss of succinylcholine chloride occurs under typicalcommercial storage conditions.

The objective of the present invention is to increase the stability ofsuccinylcholine chloride solution enabling stable injectable solutiondosage forms which can remain stable at room temperature for prolongedduration. Another objective of the present invention is to provideinjectable solutions of succinylcholine chloride which remain stablewhen stored at room temperature for prolonged duration withoutsignificant loss of potency. Yet another objective of the presentinvention is to provide stable injectable solutions of succinylcholinechloride which can be easily distinguishable from look-a-like injectionswhen placed in emergency resuscitation carts and having stability forprolonged duration without significant loss of potency, when stored atroom temperature.

The inventive pharmaceutical compositions described herein are providedin the form of a solution suitable for injection. To prepare suchcomposition, active drug is dissolved in a parenterally acceptableliquid vehicle. The pharmaceutically acceptable liquid vehicle orsolvent may comprise water, water for injection, saline, dextrosesolution, dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide,ringer's solution, isotonic sodium chloride solution, or suitablemixtures thereof.

According to the present invention, the compositions may be provided ina kit form along with a parenterally acceptable diluent. Parenterallyacceptable diluents include water for injection, 0.9% saline (normalsaline), 0.45% saline (half normal saline) and 2.5% dextrose/0.45%saline, ringer's lactate solution or mixtures thereof.

The present invention relates to injectable solution of succinylcholinechloride, particularly wherein succinylcholine chloride may be presentat a concentration of 5 mg/mL or more. In another embodiment, stableinjectable pharmaceutical compositions of the present invention comprisesuccinylcholine chloride, wherein succinylcholine chloride is present atconcentration about 5 mg/mL to about 60 mg/mL, such as about 20 mg/mL.

Preferably, the stable pharmaceutical compositions for human use will beprovided as a solution dosage form that is suitable for intravenousadministration. The pharmaceutical compositions may be formulatedaccording to conventional pharmaceutical practice. The compositions ofthe invention can be administered in any conventional manner. It will bereadily appreciated by those skilled in the art how to administercompositions of the present invention to a human.

Stabilizing agents increase the stability of succinylcholine chloride inpharmaceutically acceptable vehicles. Succinylcholine chloride ishydrolytic in nature. Stabilizing agents markedly increase the stabilityof succinylcholine chloride in aqueous solutions. Stabilizing agents areselected from the group consisting of aliphatic polyols; lower alkylalcohols; amino acids having at least one additional amino, carboxyl orhydroxyl group; amino alcohols; aliphatic dicarboxylic acids having atleast one hydroxyl or amino group, or α-β unsaturation; and mixturesthereof.

Aliphatic polyols include aliphatic acyclic or cyclic compound havingtwo or more hydroxy groups, such as glycerols, glycols and polymersthereof, and cyclic oligosaccharides. Examples of such polyols includepropylene glycol, polyethylene glycol (e.g. polyethylene glycol 300,polyethylene glycol 400, polyethylene glycol 600), cyclodextrin,cyclodextrin derivatives, and mixtures thereof.

Lower alkyl alcohols include, ethanol, propanol, isopropanol, butanol,and the like.

Amino acids having at least one additional amino, carboxyl or hydroxylgroup include glutamic acid, aspartic acid, arginine, lysine, andmixtures thereof.

Amino alcohols include meglumine, diethanolamine, tromethamine, andmixtures thereof

Aliphatic dicarboxylic acids having at least one hydroxyl or aminogroup, or α-β unsaturation maleic acid, tartaric acid, and the like.

Cyclodextrins include α-cyclodextrin, β-cyclodextrin, δ-cyclodextrin,γ-cyclodextrin, or combinations thereof. In an embodiment, thecyclodextrin includes either a substituted or non-substitutedβ-cyclodextrin, particularly hydroxypropyl-β-cyclodextrin (HP-β-CD)and/or sulfobutylether-β-cyclodextrin (SBE-β-CD). However, it isunderstood that typically any substitution to the cyclodextrin,including substitution by hydrophobic groups such as hydroxyalkylsubstituted-cyclodextrin, will improve its aqueous solubility bydisrupting the hydrogen bonding network within the crystal lattice ofthe solid cyclodextrin, thereby lowering the lattice energy of thesolid. The degree of substitution is not believed to be critical;however, the degree of substitution is advantageously at least 1% andtypically 2% to 10%, such as 3% to 6%.

In an embodiment, the present invention provides stable injectablepharmaceutical composition comprising (a) therapeutically effectiveamount of succinylcholine chloride; (b) one or more pharmaceuticallyacceptable solvents; (c) one or more stabilizing agents selected frommaleic acid, tartaric acid, glutamic acid, aspartic acid, propyleneglycol, polyethylene glycol, ethanol, glycerine, arginine, lysine,meglumine, cyclodextrin derivatives, diethanolamine, tromethamine, andmixtures thereof; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein the concentration of stabilizing agent inthe composition is less than about 300 mg/mL.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutical acceptablesolvents; (c) one or more stabilizing agents and (d) optionally, one ormore additional pharmaceutically acceptable excipients, wherein thecomposition has a pH in the range of about 3.0 to about 5.0, such as inthe range from about 3.0 to 4.5.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutical acceptablesolvents; (c) one or more stabilizing agents and (d) optionally, one ormore additional pharmaceutically acceptable excipients, wherein thecomposition has osmolality value of between about 100 mOsm and about4000 mOsm.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein thecomposition is stable when stored at room temperature conditions forprolonged duration without significant loss of potency.

The pharmaceutically acceptable excipient(s) may be selected from, butare not limited to, co-solvents, surfactants, wetting agents, waterimmiscible solvents, water, water miscible solvents, hydrophilicsolvents, hydrophobic solvents, preservatives, chelating agents,antioxidants, tonicity contributing agents, anti-foaming agents,buffering agents, pH adjusting agents, osmotic agents and the like ormixtures thereof.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein thecomposition is stable for at least 15 days, for at least 30 days, for atleast 60 days, or for at least 90 days when stored at 25° C./60% RH or25° C./40% RH.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein thecomposition is stable for at least 3 months, for at least 6 months, forat least 9 months, for at least 12 months, for at least 18 months, forat least 24 months, for at least 30 months, or for at least 36 months,when stored at 2° C. to 8° C.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein thecomposition is stable for up to 90 days when stored at 25° C.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein saidcomposition is stable at 2-8° C. for at least 18 months followed bystorage at 25° C. for at least 30 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofeach impurity in the composition is less than about 8% w/w, preferablyless than about 6% w/w, more preferably less than about 5% w/w, morepreferably less than about 2% w/w, more preferably less than about 1%w/w, more preferably less than about 0.1% w/w, more preferably less thanabout 0.1% w/w as measured by HPLC.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofsuccinic acid impurity is less than about 0.5% (w/w) as measured byHPLC, when stored at 25° C./40% RH for up to 90 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofsuccinylmonocholine impurity is less than about 5.0% (w/w) as measuredby HPLC, when stored at 25° C./40% RH for up to 90 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofcholine impurity is less than about 3.0% (w/w) as measured by HPLC, whenstored at 25° C./40% RH for up to 90 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level oftotal impurity is less than about 6.0% (w/w) as measured by HPLC, whenstored at 25° C./40% RH for up to 90 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofany unspecified impurity is less than about 0.2% (w/w) as measured byHPLC, when stored at 25° C./40% RH for up to 90 days.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein the level ofany unidentified impurity is less than about 0.2% (w/w) as measured byHPLC, when stored at 25° C./40% RH for up to 90 days.

In one embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein in saidcomposition upon intravenous or intramuscular administration exhibitsbioequivalence to a commercially available reference succinylcholinechloride drug products (such as ANECTIN® and QUELICIN®), and whereinsaid bioequivalence is established by at least one of: (i) a confidenceinterval for mean AUC_(0-t) between about 80% and about 125%; (ii) aconfidence interval for mean AUC_(0-infinity) between about 80% andabout 125%; (iii) a confidence interval for mean C_(max) between about80% and about 125% or a combination thereof.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutical acceptablesolvents; (c) one or more stabilizing agents (e) at least one pHadjusting agent and (f) optionally, one or more additionalpharmaceutically acceptable excipients, wherein said composition is freeof tonicity contributing agent.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) succinylcholine chloride at a concentrationof 20 mg/mL; (b) water for injection; (c) propylene glycol; and (d)optionally, one or more additional pharmaceutically acceptableexcipients.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) propylene glycol;and (d) optionally, one or more additional pharmaceutically acceptableexcipients; wherein the composition is free of sodium chloride.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) propylene glycol;and (d) optionally, one or more additional pharmaceutically acceptableexcipients; wherein propylene glycol is present at a concentration ofless than about 300 mg/mL.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) propylene glycol;(d) polyethylene glycol and (e) optionally, one or more additionalpharmaceutically acceptable excipients.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) polyethyleneglycol and (d) optionally, one or more additional pharmaceuticallyacceptable excipients, wherein polyethylene glycol is present at aconcentration of more than 20 mg/mL.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) ethanol and (d)optionally, one or more additional pharmaceutically acceptableexcipients, wherein ethanol is present at a concentration of more than20 mg/mL.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) propylene glycol;(d) hydroxypropyl-β-cyclodextrin (HP-β-CD) and/orsulfobutylether-β-cyclodextrin (SBE-β-CD); and (e) optionally, one ormore additional pharmaceutically acceptable excipients.

In an embodiment, the stable injectable pharmaceutical composition ofthe invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) one or morestabilizing agents and (d) optionally, one or more additionalpharmaceutically acceptable excipients, wherein molar ratio ofsuccinylcholine chloride to stabilizing agent is from about 0.5:1 to0.5:50.

In an embodiment of the invention, the stable injectable pharmaceuticalcomposition comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) water for injection; (c) one or morestabilizing agents and (d) optionally, one or more additionalpharmaceutically acceptable excipients, wherein molar ratio ofsuccinylcholine chloride to stabilizing agent is from about 1:0.5 to50:1.

In an embodiment, the pharmaceutical composition according to theinvention comprises succinylcholine chloride and propylene glycol,wherein molar ratio of succinylcholine chloride to propylene glycol isfrom 0.5:1 to 0.5:20.

In an embodiment, the pharmaceutical composition according to theinvention comprises succinylcholine chloride and polyethylene glycol,wherein molar ratio of succinylcholine chloride to polyethylene glycolis from 1:0.1 to 10:0.1.

In an embodiment, the pharmaceutical composition according to theinvention comprises succinylcholine chloride and ethanol, wherein molarratio of succinylcholine chloride to ethanol is from 1:0.1 to 10:0.1.

The pharmaceutical compositions of the present invention may optionallycontain a buffering agent, which is used to resist change in pH upondilution or addition of acid or alkali. Such compounds include, by wayof example and without limitation, succinic acid, sodium dihydrogenphosphate monohydrate, disodium hydrogen phosphate anhydrous, aceticacid, sodium acetate, adipic acid, benzoic acid, sodium benzoate,monobasic sodium phosphate, dibasic sodium phosphate, disodium hydrogenphosphate dodecahydrate, lactic acid, tris buffer, tartaric acid,potassium metaphosphate, potassium phosphate, monobasic sodium acetate,sodium bicarbonate, sodium tartrate and other buffers known to those ofordinary skill in the art.

The pharmaceutical compositions of the present invention mayadditionally contain a “tonicity contributing agent” that can be used toadjust the tonicity of the liquid formulation. Suitable tonicitycontributing agents include lactose, mannitol, dextrose, sodiumchloride, sodium sulphate, sorbitol, trehalose, xylitol, sucrose,maltose and other tonicity contributing agents known to those orordinary skill in the art. In one embodiment, the tonicity of the liquidformulation approximates that of the tonicity of blood or plasma. Theamount of tonicity contributing agent may range from about 1 mg/mL toabout 50 mg/mL of the composition.

The pharmaceutical compositions of the present invention mayadditionally contain a chelating agent, which may be selected from thegroup consisting of ethylene-diaminetetraacetic acid (EDTA),diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-tetra acetic acid (EGTA), N-(hydroxyethyl)ethylene-diaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA),triethanolamine, 8-hydroxyquinoline, phosphoric acid, gluconic acid,saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid,lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerine,sorbitol and pharmaceutically acceptable salts thereof. In someembodiments, the chelating agent is selected from the group consistingof EDTA, DTPA, phosphoric acid, gluconic acid and a pharmaceuticallyacceptable salt thereof.

The pharmaceutical compositions of the present invention mayadditionally contain an antioxidant which inhibits oxidation, and thusis used to prevent the deterioration of preparations by oxidativeprocesses. Such compounds include by way of example and withoutlimitation, acetone, sodium bisulfate, ascorbic acid, ascorbylpalmitate, citric acid, glycine, L-cysteine hydrochloride, L-methionine,butylated hydroxy anisole, butylated hydroxytoluene, hydro phosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrateanhydrous, sodium citrate dihydrate, sodium sulfide, sodium sulfite,sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid,sodium metabisulfite and other antioxidants known to those of ordinaryskill in the art. The amount of antioxidant may range from about 0.1mg/mL to about 50 mg/mL of the composition, and preferably from about0.5 mg/mL to about 25 mg/mL.

The pharmaceutical compositions of the present invention mayadditionally contain a preservative, which may be selected from thegroup consisting of benzoic acid, and sodium and potassium saltsthereof; sorbic acid, and sodium and potassium salts thereof;chlorobutanol; benzyl alcohol; phenyl ethanol; methyl, ethyl, propyl orbutyl-p-hydroxybenzoates; phenol; m-cresol; p-chloro-m-cresol;phenylmercury nitrate; benzalkonium chloride; and mixtures thereof.

The pharmaceutical compositions of the present invention mayadditionally contain pH adjusting agents. The pH adjusting agents may beselected from the group consisting of hydrochloric acid, sodiumhydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate,tromethamine, sodium linoleate, sodium oleate, potassium carbonate,potassium linoleate, potassium oleate, and mixtures thereof. In oneembodiment of the invention, the pharmaceutical composition comprisingsuccinylcholine chloride can be formulated at any suitable pH. The pH ofthe pharmaceutical composition may range from about 3 to about 5, fromabout 3.0 to about 4.5, such as about 3.6, when measured at roomtemperature. In one embodiment of the invention, pharmaceuticalcomposition comprising succinylcholine chloride can be formulated usingany suitable pH adjusting agent. In some embodiments, it is possible tomaintain the pH of the composition without using a suitable bufferingagent.

The pharmaceutical compositions of the present invention mayadditionally contain anti-foaming agents. The anti-foaming agents may beselected from the group consisting of sodium carboxymethylcellulose,sorbitol, mannitol, polyvinylpyrrolidone (PVP), polyoxyethylene sorbitanmonolaurate or monooleate, polysorbates or Tween 20 and 80,polyoxyethylene/polyoxypropylene/polyoxyethylene copolymer (PluronicL-62), glycerol polyethylene glycol ricinoleate (Cremophor EL), siliconeantifoam (Dimethicone), sorbitan monooleate or monolaurate (Span 20 and80), propylene glycol; polyethylene glycol 300 (PEG), ethanol, dimethylacetamide (DMA), glycerol, N-methyl-2-pyrrolidone, monothioglycerol, andmixtures thereof.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprising succinylcholine chloride has a viscosityvalue of about 1 cP (centipoise) to about 5 cP, for example, 1.5 cP, 2cP, 2.5 cP, 3 cP, 3.5 cP, 4 cP or 4.5 cP.

In another embodiment, the stable injectable pharmaceutical compositioncomprising succinylcholine chloride according to the present inventionhas an osmolality value of between about 100 mOsm and about 4000 mOsm,for example, about 100 mOsm, about 150 mOsm, about 200 mOsm, about 250mOsm, about 300 mOsm, about 350 mOsm, about 400 mOsm, about 450 mOsm,about 500 mOsm, about 550 mOsm, about 600 mOsm, about 650 mOsm, about700 mOsm, about 750 mOsm, about 800 mOsm, about 850 mOsm, about 900mOsm, about 950 mOsm, about 1000 mOsm, about 1100 mOsm, about 1150 mOsm,about 1200 mOsm, about 1250 mOsm, about 1300 mOsm, about 1350 mOsm,about 1400 mOsm, about 1450 mOsm, about 1500 mOsm, about 1550 mOsm,about 1600 mOsm, about 1650 mOsm, about 1700 mOsm, about 1750 mOsm,about 1800 mOsm, about 1850 mOsm, about 1900 mOsm, about 1950 mOsm,about 2000 mOsm, about 2200 mOsm, about 2300 mOsm, about 2400 mOsm,about 2500 mOsm, about 2600 mOsm, about 2700 mOsm, about 2800 mOsm,about 2900 mOsm, about 3000 mOsm, about 3100 mOsm, about 3200 mOsm,about 3300 mOsm, about 3400 mOsm, about 3500 mOsm, about 3600 mOsm,about 3700 mOsm, about 3800 mOsm, about 3900 mOsm, or about 4000 mOsm.

In yet another embodiment, the present invention relates to method ofusing the inventive compositions as an adjunct to general anesthesia, tofacilitate tracheal intubation, and to provide skeletal musclerelaxation during surgery or mechanical ventilation in a human subject,the method comprising administering to the human subject the inventivecomposition comprising succinylcholine chloride, wherein the compositionexhibits rapid onset of action and provides faster muscle relaxation.

According to yet another embodiment, the present invention providesstable injectable pharmaceutical composition of succinylcholine chlorideat concentrations higher than 5 mg/mL and methods of preparing suchsolutions. In particular, the present invention provides stable aqueoussuccinylcholine chloride solutions for parenteral administration atconcentrations about 5 mg/mL, about 5.5 mg/mL, about 6 mg/mL, about 6.5mg/mL, about 7 mg/mL, about 7.5 mg/mL, about 8 mg/mL, about 8.5 mg/mL,about 9 mg/mL, about 9.5 mg/mL, about 10 mg/mL, about 10.5 mg/mL, about11 mg/mL, about 11.5 mg/mL, about 12 mg/mL, about 12.5 mg/mL, about 13mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 14.5 mg/mL, about 15mg/mL, about 15.5 mg/mL, about 16 mg/mL, about 16.5 mg/mL, about 17mg/mL, about 17.5 mg/mL, about 18 mg/mL, about 18.5 mg/mL, about 19mg/mL, about 19.5 mg/mL, about 20 mg/mL, about 20.5 mg/mL, about 21mg/mL, about 21.5 mg/mL, about 22 mg/mL, about 22.5 mg/mL, about 23mg/mL, about 23.5 mg/mL, about 24 mg/mL, about 24.5 mg/mL, about 25mg/mL, about 25.5 mg/mL, about 26 mg/mL, about 26.5 mg/mL, about 27mg/mL, about 27.5 mg/mL, about 28 mg/mL about 28.5 mg/mL, about 29mg/mL, about 29.5 mg/mL and about 30 mg/mL.

The unit dose of the succinylcholine chloride will be in the range fromabout 1 to about 200 mg. Exemplary unit doses of succinylcholinechloride range from 1 mg to 200 mg, including unit dosages of 1 mg, 2.5mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg,27.5 mg, 30 mg, 32.5 mg, 35 mg, 40 mg, 42.5 mg, 45 mg, 50 mg, 52.5 mg,55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 70 mg, 72.5 mg, 75 mg, 80 mg,82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg, 97.5 mg, 100 mg, 102.5mg, 105 mg, 107.5 mg, 110 mg, 112.5 mg, 115 mg, 117.5 mg, 120 mg, 122.5mg, 125 mg, 127.5 mg, 130 mg, 132.5 mg, 135 mg, 140 mg, 142.5 mg, 145mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg, 162.5 mg, 165 mg, 170mg, 172.5 mg, 175 mg, 180 mg, 182.5 mg, 185 mg, 187.5 mg, 190 mg, 192.5mg, 195 mg, 197.5 mg and 200 mg, wherein unit dose may be packed in avial, ampoule, pre-filled syringe, cartridge or auto-injector.

In certain embodiment of the invention, the stable injectable solutioncomprising therapeutically effective amount of succinylcholine chloridemay provide onset of action of less than 2 minutes, for example, lessthan 1 minute, less than 40 seconds, less than 30 seconds, or less than20 seconds, when the solution is administered via intravenous orintramuscular route to a human at a succinylcholine chloride dosebetween about 1 mg and about 300 mg. The solution comprisingtherapeutically effective amount of succinylcholine chloride of theinvention provides immediate availability of the entire dose ofsuccinylcholine chloride in the blood when the solution is administeredvia intravenous or intramuscular route to a human.

In a further embodiment of the invention, the stable injectablepharmaceutical composition comprising succinylcholine chloride mayprovide a value of C_(max) of more than 0.5 μg/mL, for example, morethan 0.5 μg/mL, more than 1 μg/mL, more than 1.5 μg/mL, more than 2μg/mL, more than 2.5 μg/mL, more than 3 μg/mL, more than 3.5 μg/mL, morethan 4 μg/mL, more than 4.5 μg/mL, more than 5 μg/mL, more than 5.5μg/mL, more than 6 μg/mL, more than 6.5 μg/mL, more than 7 μg/mL, morethan 7.5 μg/mL, more than 8 μg/mL, more than 8.5 μg/mL, more than 9μg/mL, more than 9.5 μg/mL, more than 10 μg/mL, more than 15 μg/mL, morethan 20 μg/mL, more than 25 μg/mL, more than 30 μg/mL, more than 35μg/mL, more than 40 μg/mL, more than 45 μg/mL, more than 50 μg/mL, morethan 55 μg/mL, more than 60 μg/mL, more than 65 μg/mL, more than 70μg/mL, more than 75 μg/mL, more than 80 μg/mL, more than 85 μg/mL, morethan 90 μg/mL, more than 95 μg/mL, or more than 100 μg/mL, when thecomposition is administered via parenteral route to a subject at asuccinylcholine chloride dose of between about 1 mg and about 300 mg.

In a further embodiment, the stable injectable pharmaceuticalcomposition comprising succinylcholine chloride may provide a value ofAUC of more than 10 μg*h/mL, more than 20 μg*h/mL, more than 30 μg*h/mL,more than 40 μg*h/mL, more than 50 μg*h/mL, more than 60 μg*h/mL, morethan 70 μg*h/mL, more than 80 μg*h/mL, more than 90 μg*h/mL, more than100 μg*h/mL, more than 150 μg*h/mL, more than 200 μg*h/mL, more than 250μg*h/mL, more than 300 μg*h/mL, more than 350 μg*h/mL, more than 400μg*h/mL, more than 450 μg*h/mL, more than 500 μg*h/mL, more than 550μg*h/mL, more than 600 μg*h/mL, more than 650 μg*h/mL, more than 700μg*h/mL, more than 750 μg*h/mL, more than 800 μg*h/mL, more than 850μg*h/mL, more than 900 μg*h/mL, more than 950 μg*h/mL, more than 1000μg*h/mL, more than 1050 μg*h/mL, more than 1100 μg*h/mL, more than 1150μg*h/mL, or more than 2000 μg*h/mL, when the composition is administeredvia parenteral route to a subject at a succinylcholine chloride dose ofbetween about 1 mg and about 300 mg.

In another embodiment, the stable injectable pharmaceutical compositionof the invention comprises (a) therapeutically effective amount ofsuccinylcholine chloride; (b) one or more pharmaceutically acceptablesolvents; (c) one or more stabilizing agents; and (d) optionally, one ormore other pharmaceutically acceptable excipients, wherein thecomposition is disposed in a pre-filled syringe or a vial.

In an embodiment of the invention, the stable injectable pharmaceuticalcomposition disposed in a pre-filled syringe comprises; (a)therapeutically effective amount of succinylcholine chloride; (b) one ormore pharmaceutically acceptable solvents; (c) one or more stabilizingagents; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein the composition in said pre-filledsyringe is stable at 25° C. for at least 30 days.

In an embodiment of the invention, the stable injectable pharmaceuticalcomposition disposed in a pre-filled syringe comprises; (a)therapeutically effective amount of succinylcholine chloride; (b) one ormore pharmaceutically acceptable solvents; (c) one or more stabilizingagents; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein said composition is free of tonicitycontributing agent.

In an embodiment of the invention, the stable injectable pharmaceuticalcomposition disposed in a pre-filled syringe comprises; (a)succinylcholine chloride at a concentration of about 20 mg/mL; (b)purified water; (c) propylene glycol; wherein said composition is freeof sodium chloride and wherein the composition in said pre-filledsyringe is stable at 25° C. for at least 30 days.

In another embodiment of the invention, the sterile stable injectablepharmaceutical composition comprises (a) therapeutically effectiveamount of succinylcholine chloride; (b) one or more pharmaceuticallyacceptable solvents; (c) one or more stabilizing agents; and (d)optionally, one or more other pharmaceutically acceptable excipients,wherein the composition is sterilized using aseptic filtrationtechnique.

In another embodiment of the invention, the sterile stable injectablepharmaceutical composition comprises (a) therapeutically effectiveamount of succinylcholine chloride; (b) one or more pharmaceuticallyacceptable solvents; (c) one or more stabilizing agents; and (d)optionally, one or more other pharmaceutically acceptable excipients,wherein said composition contains no overage of succinylcholinechloride.

In certain embodiment, the invention relates to methods for making acomposition of the invention comprising: (i) dispensing 80% v/v of waterfor injection; (ii) sequentially adding stabilizing agent and stirringto form solution-1; (iii) adding succinylcholine chloride to solution-1and stirring to form solution-2; (iv) adjusting the pH of the solution-2by adding a suitable pH adjusting agent; (v) making up the final volumewith remaining water for injection to obtain final solution; (vi)purging the nitrogen gas throughout the procedure; (vii) filtering thefinal solution; and (viii) filling the solution in syringes or vials andstoppering with coated stoppers.

As used herein, “sterilization” refers to any physical or chemicalprocess which destroys all life forms, with special regard tomicroorganisms (including bacteria and sporogenous forms), andinactivates viruses.

As used herein, “terminal sterilization” refers to a sterilizationprocess that takes place after that the product to be sterilized hasbeen filled into at least its primary packaging. Terminal sterilizationpresents the advantage of avoiding further opportunities forcontamination of the product due to human intervention.

As used herein, “heat sterilization” refers to a sterilization processachieved by exposing the product to be sterilized to heat. As usedherein, “steam sterilization” refers to a sterilization process achievedby exposing the product to be sterilized with saturated steam.

Certain embodiments additionally relate to sterilizing the finishedproducts, e.g., aseptic filtration-filling-sealing, terminalsterilization, incorporation of sterilizing agents, irradiation, and/orheating.

Sterilization may be accomplished by any of the conventional methodsincluding aseptic filling, irradiation and heat sterilization. Heatsterilization is normally performed using steam, preferably wet steam toallow for the use of pressure as a means of temperature control. Thetime period for the sterilization must be long enough to meet thesterility requirements required of an injectable product. When steam isused, the period may be from about 5 to 30 minutes at temperatures ofabout 110° C. to 130° C., or from about 10 to 30 minutes at temperaturesof about 110° C. to 130° C., or from about 15 to 30 minutes attemperatures of about 120° C. to 125° C. In another embodiment, thesterilization can be performed at 120° C. for 5 to 15 minutes.

A pharmaceutically inert gas may be bubbled into the solution to driveout oxygen, which may be selected from nitrogen or carbon dioxide.Preferably, the solution was kept under nitrogen or carbon dioxidesparging until dissolved oxygen is less than 10 mg/L in the finalsolution.

Containers suitable according to the present invention are those knownin the art and include vials, cartridges, pre-filled syringes,auto-injectors, infusion bags, bottles and ampoule presentations.Containers may be fabricated from glass or from polymeric materials.Suitable containers should be of a size sufficient to hold one or moredoses of succinylcholine chloride.

The present invention provides for stable injectable pharmaceuticalcomposition of succinylcholine chloride in single-dose and/or multi-dosecompositions. In some embodiments, the composition may be contained invials or pre-filled syringes. In some embodiments, the vials may be madefrom clear glass, amber glass, or plastic. In some embodiments, thevials or pre-filled syringes may have a capacity in the range of about0.1 mL to 100 mL in volume, about 1 mL to 50 mL, about 1 mL to 10 mL, orabout 1 mL to 5 mL. In some embodiments, the composition may exist in a5 mL single-dose pre-filled syringe. In some embodiments, a 5 mL vialmay include a single-dose formulation. In some embodiments, a 10 mL vialmay include a single-dose formulation. In some embodiments, the 10 mLvial may have a multi-dose formulation. In some embodiments, the samevial may be used for multiple applications of the composition for up toabout 10 days, about 15 days, about 30 days, about 45 days, or about 60days after initial use.

The polymeric materials which may be used for the pre-filled syringeinclude: polysulfone, polycarbonate, polypropylene, polyethylene((low-density polyethylene or high-density polyethylene),ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers,polyester (e.g. polyethylene terephthalate, polyethylene naphthalate andthe like), Teflon™, Nylon, acetal (Delrin), polymethylpentene,polyvinylidene chloride, ethylvinylacetate, AN-copolymer etc. Inaddition, cyclic olefin copolymer (COC), cyclic olefin polymer (COP),crystal zenith (CZ) resin containers and similar resins can be used asrigid containers and syringes.

A pre-filled syringe comprising stable injectable pharmaceuticalcomposition of succinylcholine chloride according to the invention isadvantageous, as compared to vials or ampoules. A pre-filled syringefabricated from a polymer is not only be convenient for handling,storage and administration, but also minimizes mixing or dosing errors.The pre-filled syringe according to the invention may be included in asingle use auto injectors and reusable auto injectors. The pre-filledsyringe contains various constituent parts, for example, a sterile clearUSP Type-I siliconized glass syringe barrel (1 mL, cut flange with agauge (29 size), hypodermic needle (½ inch) fitted with rigid needleshield and laminated bromobutyl plunger stopper for the barrel.

In a pre-filled syringe, the drug and diluent may be in constant contactwith the components like the piston and nozzle cap for months or years.Increasing prevalence of drugs which can bind to the surface of glasssurfaces also causes problems in stability. Additionally, glass isbreakable and requires more care when filling and handling. Further, theglass pre-filled syringe presents design and manufacturing challenges.

Plastic pre-filled syringe offers a true benefit over glass syringe.Plastic pre-filled syringe provides robustness and is also lightweight,while delivering enough stability. Plastic pre-filled syringesadvantageously help improve chemical stability of otherwise relativelylabile compounds (e.g., succinylcholine) under refrigerated conditions(about 2° C. to about 8° C., or about 5° C.) and at room temperature(about 25° C.). Further advantages are simple disposal, dosage precisionand reduction of medical waste.

Further, pre-filled glass syringes can become clogged and malfunctionduring the process of connecting them to pin-activated needleless IVaccess systems. Unfortunately, such failure is not detected until afterthe syringe is inserted into the pin-activated needleless intravenousaccess system. For example, the action of inserting the syringe cancause the pin in the access system to clog or break off in the syringetip, thus preventing delivery of the medication and necessitatingplacement of a new intravenous access line. As a consequence, USFDA hasadvised that the use of needleless pre-filled glass syringes inemergency situations should be avoided. Plastic pre-filled syringesprovide solution to the problem of clogging or breakage of syringe tipand facilitates administration of succinylcholine safely in EmergencyRoom (ER) or Operating Room (OR) settings.

In an embodiment, improved stability is contemplated where the inventivesuccinylcholine composition is stored in a pre-filled plastic syringe atabout 2-8° C. or at 25° C. For example, Succinylmonocholine chlorideimpurity may be present in a range between 0.1-3%, after storinginventive succinylcholine composition in a pre-filled plastic syringe atabout 25° C. for 15-60 days or more than 60 days.

In some embodiments, the inventive succinylcholine composition disposedin a pre-filled plastic syringe contains not more than about 6% totalimpurities after storage at 2-8° C. for at least 2 months, for at least3 months, at least 6 months, at least 9 months, at least 12 months, atleast 15 months, at least 18 months, at least 21 months, at least 24months, at least 30 months, or at least 36 months as determined by HPLC,and in other embodiments the inventive succinylcholine compositiondisposed in a pre-filled plastic syringe contains not more than about 5%succinylmonocholine chloride impurity after storage at 2-8° C. for atleast 2 months, for at least 3 months, at least 6 months, at least 9months, at least 12 months, at least 15 months, at least 18 months, atleast 21 months, at least 24 months, at least 30 months, or at least 36months as determined by HPLC. In further embodiments, the inventivesuccinylcholine composition disposed in the pre-filled plastic syringecontains not more than about 0.5% succinic acid impurity after storageat 2-8° C. for at least 2 months, for at least 3 months, at least 6months, at least 9 months, at least 12 months, at least 15 months, atleast 18 months, at least 21 months, at least 24 months, at least 30months, or at least 36 months as determined by HPLC. In furtherembodiments, the inventive succinylcholine composition disposed in thepre-filled plastic syringe contains not more than about 3% cholineimpurity after storage at 2-8° C. for at least 2 months, for at least 3months, at least 6 months, at least 9 months, at least 12 months, atleast 15 months, at least 18 months, at least 21 months, at least 24months, at least 30 months, or at least 36 months as determined by HPLC.

In some embodiments, the inventive succinylcholine composition disposedin a pre-filled plastic syringe contains not more than about 6% totalimpurities after storage at 25° C./60% RH or 25° C./40% RH or at roomtemperature for at least 2 months, for at least 3 months, at least 6months, at least 9 months, at least 12 months, at least 15 months, atleast 18 months, at least 21 months, at least 24 months, at least 30months, or at least 36 months as determined by HPLC. In otherembodiments, the inventive succinylcholine composition disposed in apre-filled plastic syringe contains not more than about 5%succinylmonocholine chloride impurity after storage at 25° C./60% RH or25° C./40% RH or at room temperature for at least 2 months, for at least3 months, at least 6 months, at least 9 months, at least 12 months, atleast 15 months, at least 18 months, at least 21 months, at least 24months, at least 30 months, or at least 36 months as determined by HPLC.In further embodiments, the inventive succinylcholine compositiondisposed in the pre-filled plastic syringe contains not more than about0.5% succinic acid impurity after storage at 25° C./60% RH or 25° C./40%RH or at room temperature for at least 2 months, for at least 3 months,at least 6 months, at least 9 months, at least 12 months, at least 15months, at least 18 months, at least 21 months, at least 24 months, atleast 30 months or at least 36 months as determined by HPLC. In furtherembodiments, the inventive succinylcholine composition disposed in thepre-filled plastic syringe contains not more than about 3% cholineimpurity after storage at 25° C./60% RH or 25° C./40% RH or at roomtemperature for at least 2 months, for at least 3 months, at least 6months, at least 9 months, at least 12 months, at least 15 months, atleast 18 months, at least 21 months, at least 24 months, at least 30months, or at least 36 months as determined by HPLC.

In an embodiment, the present invention provides a kit comprising anauto injector which contains a pre-filled syringe (a pre-filled syringeassembled/placed in the auto injector). The autoinjector may beintegrated with a needle stick protection feature and holds a pre-filledsyringe containing a single dose, whereby the entire deliverable volumeis expelled.

In an embodiment, a kit comprising a prefilled syringe or syringecartridge comprising an injectable pharmaceutical compositioncomprising; (a) therapeutically effective amount of succinylcholinechloride; (b) one or more pharmaceutically acceptable solvents; (c) oneor more stabilizing agents; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the kit furthercomprises an injection device for administration of the composition to asubject in need of such pharmaceutical composition and wherein theinjection device comprises a needle and the prefilled syringe or syringecartridge.

The stable injectable succinylcholine chloride solution preparations asdescribed herein may further comprise effective amounts of one or moreother therapeutically active ingredient.

Minimizing medication error: Currently, there is no standardizedcolor-coded labelling system in anaesthesia practice that is universallyimplemented and enforced by accrediting organizations. Inconsistenciesin labelling system can lead to misidentification of medicationsyringes, medication errors, and adverse patient outcomes.

Human error makes up an estimated 80% of medication errors in healthcare. Anesthesia providers work in high-stress situations andenvironments. The operating room is a complex environment that presentsa multitude of distractions for anesthesia providers. Syringescontaining drugs frequently utilized by anesthesia providers are manytimes instinctually recognized and chosen based on their location andvisual features. Recalling and distinguishing an object relies heavilyon shape, colour, brightness, and contrast. As these characteristicsbecome increasingly distinct, they become increasingly identifiable.Ubiquitous adoption of a standardized color-coded label on pre-filledsyringe is capable of increasing patient safety and decreasing theincidence of mediation errors through the facilitation of syringerecognition by anaesthesia providers in the perioperative period.

The objective of implementing standardized labelling is to improvepatient safety by facilitating identification of succinylcholinepre-filled syringes labelled with standardized color-coded medicationlabels. The label specifications used facilitate to identifysuccinylcholine pre-filled syringes include the size, color, content,pattern, and type of label used.

In an embodiment, stable pre-filled syringes of the invention withstandardized colour-coded medication label suitable for parenteraladministration comprises (a) succinylcholine chloride; (b) one or morepharmaceutical acceptable solvents; (c) one or more stabilizing agents(d) one or more tonicity contributing agents; (e) optionally, one ormore additional pharmaceutically acceptable excipients, wherein thestandardized colour-coded medication label facilitates properidentification of succinylcholine pre-filled syringes in Emergency Room(ER) or Operating Room (OR) settings, thereby increasing patient safetyand decreasing the incidence of mediation errors.

Stability: The terms “stable” and “stability” mean that the evolution ofthe product with time and/or under specific environmental conditions(i.e., temperature, humidity, etc.) has no significant effects on itsquality, safety and/or efficacy for a given time period. It can bemeasured through the formation of degradation products (impurities),variation of pH, appearance (precipitation), microbial growth, and/orcolor. The term “stable” indicates both chemical and physical stability.The term “stable” further means that no more than about a 10% loss ofsuccinylcholine chloride under typical commercial storage conditions.

Preferably, formulations of the present inventions will have no morethan about a 8% loss of succinylcholine chloride, more preferably, nomore than about a 5% loss of succinylcholine chloride, more preferably,no more than about a 3% loss of succinylcholine chloride upon storage atroom temperature for at least 2 months, for at least 3 months, at least6 months, at least 9 months, or at least 12 months. Preferably,formulations of the present inventions will have no more than about a 8%loss of succinylcholine chloride, more preferably, no more than about a5% loss of succinylcholine chloride, more preferably, no more than abouta 3% loss of succinylcholine chloride under storage conditions, such as25° C./60% RH or 25° C./40% RH for at least 2 months, for at least 3months, at least 6 months, at least 9 months, and at least 12 months.Preferably, formulations of the present inventions will have no morethan about a 8% loss of succinylcholine chloride, more preferably, nomore than about a 5% loss of succinylcholine chloride, more preferably,no more than about a 3% loss of succinylcholine chloride under storageconditions of 2-8° C. for at least 2 months, for at least 3 months, atleast 6 months, at least 9 months, at least 12 months, at least 15months, at least 18 months, at least 21 months, at least 24 months, atleast 30 months and at least 36 months.

In an embodiment, a stable pre-filled plastic syringe suitable forparenteral administration comprises (a) succinylcholine chloride; (b)one or more pharmaceutical acceptable solvents; (c) one or morestabilizing agents and (d) optionally, one or more additionalpharmaceutically acceptable excipients, wherein said composition isstable at 2-8° C. for at least 18 months followed by storage at 25° C.for at least 30 days.

In an embodiment, the inventive pharmaceutical compositions are stablefor up to 14 days at room temperature without significant loss ofpotency. In another embodiment, inventive pharmaceutical compositionsare stable for at least 1 month at room temperature without significantloss of potency. In yet another embodiment, inventive pharmaceuticalcompositions are stable for at least 2 months at room temperaturewithout significant loss of potency.

In certain embodiments, the inventive pharmaceutical compositions arestable for at least 1 month when stored at 25° C. and 60% RH or 25°C./40% RH. In certain embodiments, the inventive pharmaceuticalcompositions are stable for at least 2 months when stored at 25° C. and60% RH or 25° C./40% RH. In certain embodiments, the inventivepharmaceutical compositions are stable for at least 24 months whenstored at 2-8° C.

In particular, the presence of succinylmonocholine (i.e.,2-[(3-carboxypropanoyl)oxy]-N,N,N-trimethylethane-1-aminium) as animpurity may be monitored. The structure of succinylmonocholine is shownbelow:

In certain embodiments, the inventive pharmaceutical composition has alevel of succinylmonocholine impurity of less than 5%, less than 3%,less than 1%, less than 0.8%, or less than 0.4% as measured by HPLC.

In another embodiment, the stable injectable succinylcholine chloridepharmaceutical composition comprising succinylcholine chloride is clearor free of any crystals/precipitates by visual, inspection after storagefor at least 1 month, for example, 2 months, 3 months, 6 months, 12months, 18 months, or 24 months, at 2-8° C., 25° C./60% RH or 25° C./40%RH conditions. The solution of the present invention provides value ofabsorbance of not more than 1, for example, not more then 0.75, 0.5,0.4, 0.3, 0.2, 0.1 or 0.05, and value of % transmittance of not lessthan 90%, for example, not less than 95%, 96%, 97%, 98%, 99%, 99.5% or99.9%.

In another embodiment, the stable pharmaceutical composition comprisingsuccinylcholine chloride for parenteral administration does not containmore than 5% of 2-[(3-carboxypropanoyl)oxy]-N,N,N-trimethylethane-1-aminium (also known as succinylmonocholine)impurity, such as less than 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%,0.4%, 0.3%, 0.2% or 0.1%, by weight of succinylcholine chloride, asmeasured by HPLC.

In another embodiment, the stable pharmaceutical composition comprisingsuccinylcholine chloride for parenteral administration does not containmore than 3% of 2-Hydroxy-N,N,N-trimethylethane-1-aminium (also known ascholine) impurity, such as less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%,0.3%, 0.2% or 0.1%, by weight of succinylcholine chloride, as measuredby HPLC.

In another embodiment, the stable pharmaceutical composition comprisingsuccinylcholine chloride for parenteral administration does not containmore than 0.5% of butanedioic acid (also known as succinic acid)impurity, such as less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%,0.2% or 0.1%, by weight of succinylcholine chloride, as measured byHPLC.

In another embodiment, the shelf-life of a stable injectable compositionof the invention comprising succinylcholine chloride, when stored at2-8° C. in the sealed original packaging, may be between 1 month and 36months, between 6 months and 24 months, or between 12 months and 18months.

Dosage and Administration: The inventive pharmaceutical compositions asdescribed herein may be used as an adjunct to general anesthesia, tofacilitate tracheal intubation, or to provide skeletal muscle relaxationduring surgery or mechanical ventilation in which therapeuticallyeffective amount of succinylcholine chloride is administered to a humansubject.

Preferably, the present application relates to method of using theinventive compositions as an adjunct to general anesthesia, tofacilitate tracheal intubation, and to provide skeletal musclerelaxation during surgery or mechanical ventilation, the methodcomprising administering the inventive composition comprisingsuccinylcholine chloride to the human subject.

For short surgical procedures in adults, recommended optimum dose variesamong individuals and may be from 0.3 to 1.1 mg/kg succinylcholinechloride injection given intravenously to produce neuromuscular blockadeand to facilitate tracheal intubation. For long surgical procedures, thedose of succinylcholine chloride administered by infusion depends uponthe duration of the surgical procedure and the need for musclerelaxation. The average rate for an adult range between 2.5 and 4.3 mgper minute.

In an embodiment, the present invention relates to facilitating trachealintubation in a human subject, the method comprising administering 0.3to 1.1 mg/kg succinylcholine chloride given as intravenous bolusinjection to a human subject.

In one embodiment of the method as disclosed herein, the intravenous(IV) bolus dose of succinylcholine chloride is administered to thepatient over the course of about 30 seconds to about 6 minutes,including all values and sub-ranges there between. The IV dose ofsuccinylcholine chloride may be administered to a patient in about 30seconds, about 31 second, about 32 seconds, about 33 seconds, about 34seconds, about 35 second, about 36 seconds, about 37 seconds, about 38seconds, about 39 second, about 40 seconds, about 41 second, about 42seconds, about 43 seconds, about 44 seconds, about 45 second, about 46seconds, about 47 seconds, about 48 seconds, about 49 second, about 50seconds, about 51 second, about 52 seconds, about 53 seconds, about 54seconds, about 55 second, about 56 seconds, about 57 seconds, about 58seconds, about 59 second, about 1 minute, about 2 minute, about 3minute, about 4 minute, about 5 minute, about 6 minute or any rangesbetween these values.

In one embodiment, the dose of succinylcholine chloride is in the rangeof from about 0.3 mg to about 300 mg.

In some embodiments, the methods comprise administering stableinjectable succinylcholine chloride solution to a subject for a durationof about 30 seconds, about 45 seconds, about 1 minute, about 2 minutes,about 4 minutes, about 6 minutes, about 10 minutes, about 20 minutes,about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about9 hours, about 10 hours, about 11 hours, or about 12 hours.

In one embodiment, the methods disclosed herein comprise administeringto the patient a dose of succinylcholine chloride intravenously orintramuscularly, wherein the succinylcholine chloride is administered ata dose of about 0.3 mg to 300 mg. In some embodiments, the methodsdisclosed herein comprise administering to the patient a dose ofsuccinylcholine chloride intravenously or intramuscularly, wherein thesuccinylcholine chloride is at a concentration of about 1 mg/mL or 200mg/mL. In one embodiment, the intravenous dose is a bolus dose or aninfusion.

In an embodiment, the present invention relates to a method forfacilitating tracheal intubation in adult patients with intravenous doseof succinylcholine chloride ranging from 0.3 mg/kg a day to 1.1 mg/kg.

In an embodiment, the present invention relates to methods for providingmuscle relaxation in adult patients with intravenous infusion dose ofsuccinylcholine chloride ranging between 2.5 and 4.3 mg per minute.

In an embodiment, the present invention relates to methods forfacilitating tracheal intubation in pediatric patients with intravenousdose of succinylcholine chloride ranging from 1 mg/kg a day to 2 mg/kg.

In an embodiment, the present invention relates to a method forproviding muscle relaxation in pediatric patients with intramusculardose of succinylcholine chloride ranging from 3 mg/kg a day to 4 mg/kg.

In certain embodiment, the inventive pharmaceutical compositionsdescribed herein may be used to treat adults and adolescents (e.g.,about 13-17 years). In certain embodiment, the pharmaceuticalcompositions described herein may be used as monotherapy or asadjunctive therapy. For example, additional active agents may be used inadjunctive therapy with succinylcholine chloride, such as opioidmedications (e.g., morphine, hydromorphone, etc.).

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The unitdosage forms can be administered to achieve any daily amount describedherein, such as by administering one to five times daily (e.g., one,two, three, four, or five times daily).

HPLC procedure: As explained in detail below, the following HPLCprocedure was used to detect, quantify impurities of succinylcholine andto determine assay % of succinylcholine. The materials and methods arelisted below:

TABLE 1 Related substances identification by HPLC Chromatographicconditions Column Pursuit XRs C18, 250 mm × 4.6 mm, 5 μ ColumnTemperature 50° C. Flow rate 0.8 mL/min Detector 214 nm with UV detectorInjection volume 15 μL Run time 80 minutes for blank and samples Sampletemperature 10° C. Mode of elution Gradient Preparation of Buffer Weighand transfer about 3.85 g of 1-Pentane sulphonic acid sodium saltanhydrous and 2.76 g of Sodium dihydrogen phosphate monohydrate into abeaker containing 1000 mL of water and sonicate to dissolve. To this add1 mL of Orthophosphoric acid and mix well. Filter the buffer through0.45 μ membrane filter. Preparation of Organic modifier MixAcetonitrile, Methanol and Water in the ratio of 50:40:10 (% v/v/v)respectively Preparation of Mobile Phase A Prepare a mixture of Bufferand Organic modifier in the ratio of 95:5 (% v/v) and degas it for about10 minutes. Preparation of Mobile Phase B Prepare a mixture of Bufferand Organic modifier in the ratio of 30:70 (% v/v) and degas it forabout 10 minutes.

TABLE 2 Gradient program % Mobile % Mobile Time (mins) phase-A phase-B 0100 0 5 100 0 55 50 50 57 0 100 65 0 100 67 100 0 80 100 0

TABLE 3 Choline content identification by HPLC Chromatographicconditions Column Shodex ® YS-50, 125 * 4.6 mm, 5 uM Column Temperature 35° C. Flow rate 1.0 mL/min Injection volume  30 μL Run time  30minutes Sample temperature  15° C. Mode of elution Isocratic MobilePhase Formic acid

TABLE 4 Assay of Succinylcholine chloride injection by HPLCChromatographic conditions Column Zorbax RX-SIL, 250 mm × 4.6 mm, 5 μm(Part. No.: AG880975-901) or equivalent Column Temperature   25° C. Flowrate 0.75 mL/min Detector  214 nm with UV detector Injection volume   50μL Run time   20 minutes Sample temperature   10° C. Mode of elutionIsocratic Preparation of Mobile Mix 1N tetramethylammonium chloride andPhase Methanol in the ratio of 10:90 (v/v) respectively. Filter themobile phase using 0.45 μ membrane filter. Adjust the pH of the solutionto 3.0 ± 0.05 using 1N hydrochloric acid and mix well.

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

Example 1

Succinylcholine chloride compositions are set forth in Table 5, 6, 7, 8and 9.

TABLE 5 Composition Ingredients (mg/mL) 1 2 3 4 5 6 7 8 9Succinylcholine chloride 20 20 20 20 20 20 20 20 20 Sodium chloride 4.64.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 Methyl Paraben 1.8 Propyl Paraben 0.2 —— — — — — — — Maleic acid — 0.1 — — — — — — — Tartaric acid — — 0.4 — —— — — — L-Glutamic acid — — — 2.0 — — — — — L-Aspartic acid — — — — 2.0— — — — Propylene glycol — — — — — 100 300 — — PEG-300 — — — — — — — 100— PEG-400 — — — — — — — — 200 Hydrochloric acid q.s. for adjusting pH3.5 Sodium hydroxide q.s. for adjusting pH 3.5 Water for injection q.s.to 1 mL

TABLE 6 Ingredients Composition (mg/mL) 10 11 12 13 14 15 16 17 18 19Succinylcholine 20 10 20 10 20 20 20 20 20 20 chloride Propylene 300 300300 300 300 100 100 100 100 100 glycol Sodium 4.6 4.6 4.6 4.6 4.6 — — —— — chloride SBE-β-CD 160 160 — — — — — — — — HP-β-CD — — 170 170 110 —— — — — Maleic acid — — — — — — — 0.1 — — Tartaric acid — — — — — — — —0.4 — Glutamic acid — — — — — — — — — 2 Hydrochloric q.s. for adjustingpH 3.5 q.s. for q.s. for adjusting pH acid adjusting 4.3 pH 3.8 Sodiumq.s. for adjusting pH 3.5 q.s. for q.s. for adjusting pH hydroxideadjusting 4.3 pH 3.8 Water for q.s. to 1 mL injection

TABLE 7 Ingredients Composition (mg/mL) 20 21 22 23 24 25 26 27 28Succinylcholine 20 20 20 20 20 20 20 20 20 chloride Maleic acid 0.1 — —— — 0.1 — — 0.1 Tartaric acid — 0.4 — — — — 0.4 — — Glutamic acid — — 2— — — — 2 — SBE-β-CD — — — 170 — 170 170 170 170 HP-β-CD — — — — 170 — —— — PEG-300 100 100 100 — — — — — — Propylene — — — 100 100 — — — 100glycol Hydrochloric q.s. for adjusting pH 4.3 acid Sodium q.s. foradjusting pH 4.3 hydroxide Water for q.s. to 1 mL injection

TABLE 8 Ingredients Composition (mg/mL) 29 30 31 32 33 34 35 36Succinylcholine 20 20 20 20 20 20 20 20 chloride Maleic acid 0.1 0.1 — —— — — — Tartaric acid — — 0.4 — — — — — Glutamic acid — — — 2 — — — —HP-β-CD 170 170 170 170 100 170 200 250 Propylene glycol 100 — — — — — —— Hydrochloric acid q.s. for adjusting pH 4.3 q.s. for adjusting pH 4.0Sodium hydroxide q.s. for adjusting pH 4.3 q.s. for adjusting pH 4.0Water for injection q.s. to 1 mL

TABLE 9 Ingredients Composition (mg/mL) 37 38 39 40 41 42 43 44Succinylcholine 20 20 20 20 20 20 20 20 chloride Sodium chloride 4.6 4.64.6 4.6 4.6 4.6 4.6 4.6 Maleic acid 0.05 — — — — — 0.1 — Tartaric acid —0.1 0.2 — — — — — Glutamic acid — — — 0.5 1 — — — HP-β-CD — — — — — — —50 Propylene glycol — — — — — 20 20 — Hydrochloric acid q.s. foradjusting pH 3.6-3.7 Sodium hydroxide q.s. for adjustinq pH 3.6-3.7Water for injection q.s. to 1 mL

TABLE 10 Composition Ingredients (mg/mL) A B C D E F Succinylcholinechloride 20 20 20 20 20 20 Propylene glycol 300 250 200 150 100 50Hydrochloric acid q.s. for adjusting pH 3.6-3.7 Sodium hydroxide q.s.for adjusting pH 3.6-3.7 Water for injection q.s. to 1 mL

TABLE 11 Composition Ingredients (mg/mL) G H I J K L M Succinylcholine20 20 20 20 20 20 20 chloride Propylene glycol 100 300 — 50 — 150 —Polyethylene — — — 150 — — 50 glycol 300 Ethanol — — — — 120 120 120Sodium Chloride 4.6 4.6 4.6 — — — Hydrochloric acid q.s. for adjustingpH 3.6-3.7 Sodium hydroxide q.s. for adjusting pH 3.6-3.7 Water forinjection q.s. to 1 mL

Manufacturing Procedure of Compositions Set Forth in Table 5, 6, 7, 8,9, 10 and 11 is as Follows:

Required quantity of water for injection (WFI) was added tomanufacturing container and cooled it to 2-8° C. To decrease dissolvedoxygen (DO) content in WFI to below 1 ppm, nitrogen gas purging through0.2 micron filter was initiated. Under continuous nitrogen gas purging,stabilizing agent was sequentially added at a predetermined quantity (asset forth in Table 5, 6, 7, 8, 9, 10 and 11) to WFI and completelydissolved to prepare a solution. Accurately weighed quantity ofsuccinylcholine chloride was added to above solution and stirred undercontinuous nitrogen gas purging until complete dissolution. The pH ofthe solution was measured, and an appropriate amount of pH adjustingagent was added to the above solution to adjust pH to predeterminedrange (as set forth in Table 5, 6, 7, 8, 9, 10 and 11). Under continuousnitrogen gas purging, sufficient quantity of cooled WFI was added tomake up volume of solution to final composition. The pH of finalcomposition was measured. Final composition was filtered usingsterilizing grade 0.2 micron filter and collected under nitrogen gasblanketing at 2-8° C. Syringes or vials were filled with required volumeof final composition and stoppered using coated stoppers to obtainpre-filled syringes or vials which were stored at 2-8° C. Entiremanufacturing procedure was performed at 2-8° C.

Stability data of Compositions were set forth in below Tables.

TABLE 12 Composition 1 25° C./ 25° C./ Storage Condition 60% RH 40% RH2-8° C. Duration Initial 1 month Pack (MOC) — Glass PFS PFS vial (COC)(COC) Description Clear, colorless solution free from visible particlespH 3.7 3.33 3.42 NA Assay (Succinylcholine 101.4 97.9 96.5 99.8chloride) Osmolality (mOsmol/kg) 296 298 297 NA Impurities (% w/w)Succinic acid 0.084 0.042 0.044 0.005 Succinylmonocholine 0.212 1.6891.715 0.43 Choline 0.36 1.07 0.94 NP Total impurities 0.32 1.94 1.970.65 *W = Week/s; M = Month/s; MOC: Material of construction; PFS:prefilled syringe; COC: cyclic olefin copolymer; NA: Not Applicable; NP:Not performed; ND: Not detected; CZ: crystal zenith

TABLE 13 Composition 2 25° C./ 25° C./ Storage Condition 60% RH 40% RH2-8 °C Duration Initial 1 month Pack (MOC) Glass PFS PFS vial (COC)(COC) Description Clear, colorless solution free from visible particlespH 3.68 3.35 3.31 3.49 Assay (Succinylcholine 101 98.7 96.9 100.1chloride) Osmolality (mOsmol/kg) 285 286 285 284 Impurities (% w/w)Succinic acid 0.068 0.039 0.042 0.002 Succinylmonocholine 0.236 1.6231.683 0.434 Choline — 1.01 1.08 0.38 Total impurities 0.3 1.66 1.86 0.44

TABLE 14 Composition 3 25° C./ 25° C./ Storage Condition 60% RH 40% RH2-8° C. Duration Initial 1 month Pack (MOC) Glass PFS PFS vial (COC)(COC) Description Clear, colorless solution free from visible particlespH 3.51 3.35 3.35 3.41 Assay (Succinylcholine 101.40 97.0 95.6 99.7chloride) Osmolality (mOsmol/kq) 289 288 289 288 Impurities (% w/w)Succinic acid 0.07 0.044 0.013 0.003 Succinylmonocholine 0.251 1.7451.765 0.48 Choline 0.41 1.08 1.01 0.36 Total impurities 0.49 2.18 2.170.89

TABLE 15 Composition 4 25° C./ 25° C./ Storage Condition 60% RH 40% RH2-8° C. Duration Initial 1 month Pack (MOC) Glass PFS PFS vial (COC)(COC) Description Clear, colorless solution free from visible particlespH 3.50 3.38 3.38 3.42 Assay (Succinylcholine 101.4 97.7 96.2 98.9chloride) Osmolality (mOsmol/kg) 301 302 302 301 Impurities (% w/w)Succinic acid 0.07 0.045 0.043 0.006 Succinylmonocholine 0.238 1.8641.866 0.472 Choline NP 1.14 1.14 0.4 Total impurities 0.33 2.19 2.200.77

TABLE 16 Composition 5 25° C./ 25° C./ Storage Condition 60% RH 40% RH2-8° C. Duration Initial 1 month Pack (MOC) Glass PFS PFS vial (COC)(COC) Description Clear, colorless solution free from visible particlespH 3.48 3.38 3.39 3.41 Assay (Succinylcholine 100.1 96.5 97.1 100.1chloride) Osmolality (mOsmol/kq) 305 305 305 304 Impurities (% w/w)Succinic acid 0.071 0.048 0.013 0.003 Succinylmonocholine 0.274 1.9621.984 0.517 Choline NP 1.27 1.23 0.42 Total impurities 0.35 2.01 2.000.52

TABLE 17 Composition 6 25° C./ 25° C./ Storage Condition Initial 60% RH40% RH 2-8° C. Duration 1 month Pack (MOC) Glass CZ PFS Glass CZ PFSvial vial (COC) vial vial (COC) Description Clear, colorless solutionfree from visible particles pH 3.6 3.41 3.37 3.42 3.65 3.57 3.64 Assay100.1 97.4 96.3 96.5 99.0 99.2 99.0 (Succinylcholine chloride)Impurities (% w/w) Succinic acid 0.096 0.036 0.038 0.036 0.003 0.0020.004 Succinylmonocholine 0.219 1.457 1.458 1.456 0.424 0.435 0.421Choline NP NP NP 0.99 NP NP NP Total impurities 0.32 1.69 1.70 2.01 0.600.91 0.66

TABLE 18 Composition 7 25° C./ 25° C./ Storage Condition Initial 60% RH40% RH 2-8° C. Duration 1 month Pack (MOC) — Glass CZ PFS Glass CZ PFSvial vial (COC) vial vial (COC) Description Clear, colorless solutionfree from visible particles pH 3.57 3.45 3.41 3.50 3.47 3.56 3.78 Assay99.4 96.1 95.4 96.9 96.8 96.8 97.1 (Succinylcholine chloride) Impurities(% w/w) Succinic acid ND 0.025 0.026 0.024 0.002 0.006 0.003Succinylmonocholine 0.166 1.079 1.096 1.065 0.356 0.36 0.364 Choline NPNP NP 0.65 NP NP NP Total impurities 0.17 1.36 1.39 1.31 0.58 0.66 0.57

TABLE 19 Composition 8 25° C./ 25° C./ Storage Condition Initial 60% RH40% RH 2-8° C. Duration 1 month Pack (MOC) Glass CZ PFS Glass CZ PFSvial vial (COC) vial vial (COC) Description Clear, colorless solutionfree from visible particles pH 3.44 3.01 3.02 3.05 3.16 3.11 3.18 Assay(Succinylcholine 101.2 96.1 96.7 96.8 98.6 99.1 99.4 chloride)Impurities (% w/w) Succinic acid ND 0.054 0.058 0.051 0.013 0.016 0.011Succinylmonocholine 0.366 2.047 2.21 2.095 0.506 0.529 0.494 Choline0.35 NP NP 1.27 0.42 0.39 0.39 Total impurities 0.37 2.28 2.29 2.30 0.600.73 0.67

TABLE 20 Composition 9 25° C./ 25° C./ Storage Condition Initial 60% RH40% RH 2-8° C. Duration 1 month Pack (MOC) Glass CZ PFS Glass CZ PFSvial vial (COC) vial vial (COC) Description Clear, colorless solutionfree from visible particles pH 3.39 3.00 2.99 3.01 3.10 3.08 3.10 Assay(Succinylcholine 100.6 96.3 95.4 95.3 99.1 97.3 98.3 chloride)Impurities (% w/w) Succinic acid ND 0.043 0.046 0.048 0.007 ND 0.002Succinylmonocholine 0.3 2.245 2.248 2.188 0.583 0.586 0.575 Choline 0.41NP NP 1.37 0.42 0.4 0.37 Total impurities 0.3 2.29 2.29 2.28 0.61 0.590.58

TABLE 21 Composition 10 Storage Condition 25° C./60% RH Duration Initial1 month Pack (MOC) Glass CZ Amber vial vial vial Description Clear,colorless solution free from visible particles pH 3.55 3.42 3.40 3.43Assay (Succinylcholine 97.7 93.0 93.8 93.6 chloride) Osmolality(mOsmol/kq) 1112/ 1067*/ 1077*/ 1103*/ 5560 5335 5385 5515 Impurities (%w/w) Succinic acid 0.045 0.051 0.062 0.058 Succinylmonocholine 0.0251.682 1.749 1.655 Choline 0.29 NP NP NP Total impurities 0.07 1.78 1.851.76

TABLE 22 Composition 10 Storage 25° C./ Condition 40% RH 2-8° C.Duration 1 month Pack (MOC) PFS Glass CZ Amber PFS (COC) vial vial vial(COC) Description Clear, colorless solution free from visible particlespH 3.46 3.63 3.50 3.51 3.51 Assay (Suc- 94.6 96.5 97.1 96.0 96.3cinylcholine chloride) Osmolality 1083*/ 1058*/ 1082*/ 1093*/ 1068*/(mOsmol/kg) 5415 5290 5410 5465 5340 Impurities (% w/w) Succinic acid0.048 0.029 0.024 0.024 0.023 Succinyl- 1.594 0.370 0.416 0.354 0.390monocholine Choline NP NP NP NP NP Total 1.70 0.47 0.51 0.44 0.47impurities

TABLE 23 Composition 11 25° C./ Storage Condition 60% RH 2-8° C.Duration Initial 1 month Pack (MOC) Glass Glass vial vial DescriptionClear, colorless solution free from visible particles pH 3.6 3.47 3.48Assay (Succinylcholine 98 96.5 98.7 chloride) Osmolality (mOsmol/kq)1072/5360 NP NP Impurities (% w/w) Succinic acid ND 0.001 NDSuccinylmonocholine ND 1.729 0.449 Choline 0.32 NP NP Total impurities0.32 1.74 0.46

TABLE 24 Composition 12 Storage Condition 25° C./60% RH Duration Initial1 month Pack (MOC) Glass CZ Amber vial vial vial Description Clear,colorless solution free from visible particles pH 3.5 3.44 3.46 3.42Assay (Succinylcholine 99.8 97.0 97.2 97.4 chloride) Osmolality(mOsmol/kg) 1023/ NP NP NP 5115 Impurities (% w/w) Succinic acid ND0.012 0.014 0.01 Succinylmonocholine 0.025 0.945 0.964 0.928 Choline NPNP NP NP Total impurities 0.03 1.13 1.15 1.11

TABLE 25 Composition 12 Storage 25° C./ Condition 40% RH 2-8° C.Duration 1 month Pack (MOC) PFS Glass CZ Amber PFS (COC) vial vial vial(COC) Description Clear, colorless solution free from visible particlespH 3.49 3.45 3.44 3.44 3.52 Assay (Suc- 97.3 98.1 97.7 97.5 97.5cinylcholine chloride) Impurities (% w/w) Succinic acid 0.012 ND ND0.003 ND Succinyl 0.885 0.219 0.223 0.237 0.228 monocholine Choline NPNP NP NP NP Total 1.04 0.59 0.51 0.90 0.39 impurities

TABLE 26 Composition 13 25° C./ Storage Condition 60%RH 2-8° C. DurationInitial 1 M Pack (MOC) Glass Glass vial vial Description Clear,colorless solution free from visible particles pH 3.57 3.5 3.63 Assay(Succinylcholine 96.7 96.8 98.7 chloride) Osmolality (mOsmol/kq) 991/ NPNP 4955 Impurities (% w/w) Succinic acid 0.021 0.041 0.019Succinylmonocholine 0.052 1.106 0.204 Choline 0.13 NP NP Totalimpurities 0.07 1.38 0.45

TABLE 27 Composition 14 Storage Condition 25° C./ 60% RH 2-8° C.Duration 1 month 1 month Pack (MOC) Glass CZ Amber Glass CZ Amber vialvial vial vial vial vial Description Clear, colorless solution free fromvisible particles pH 3.45 3.41 3.44 3.52 3.49 3.54 Assay(Succinylcholine chloride) 96.2 95.5 95.7 97.8 97.6 97.0 Impurities (%w/w) Succinic acid 0.013 0.007 0.011 0.003 0.007 0.005Succinylmonocholine 0.973 0.994 0.978 0.219 0.208 0.216 Choline NP NP NPNP NP NP Total impurities 1.21 1.20 1.25 0.40 0.41 0.42

TABLE 28 Composition 15 25° C./ Storage Condition 60% RH 2-8° C.Duration Initial 1 month Pack (MOC) Glass Glass vial vial DescriptionClear, colorless solution free from visible particles pH 3.99 3.66 4.23Assay (Succinylcholine 101.4 101.2 101.9 chloride) Osmolality(mOsmol/kq) 312/ 313 315 1560 Impurities (% w/w) Succinic acid ND 0.0350.001 Succinylmonocholine 0.283 1.357 0.422 Choline NP 0.77 0.24 Totalimpurities 0.4 1.39 0.42

TABLE 29 Composition 16 25° C./ Storage Condition 60% RH 2-8° C.Duration Initial 2 W 2 W Pack (MOC) Glass Glass vial vial DescriptionClear, colorless solution free from visible particles pH 4.42 3.77 4.11Assay (Succinylcholine 98.8 96.0 96.7 chloride) Osmolality (mOsmol/kg)307/ NP NP 1535 Impurities (% w/w) Succinic acid ND 0.012 NDSuccinylmonocholine 0.379 1.017 0.491 Choline NP NP NP Total impurities0.58 1.51 0.90

TABLE 30 Composition 17 Storage Condition Initial 25° C./60% RH 2-8° C.Duration 2 W 2 W Pack (MOC) Glass vial Glass vial Description Clear,colorless solution free from visible particles pH 4.24 3.81 4.16 Assay(Succinylcholine 99.8 98.2 99.8 chloride) Osmolality 307/1535 NP NP(mOsmol/kg) Impurities (% w/w) Succinic acid ND 0.008 NDSuccinylmonocholine 0.335 1.055 0.459 Choline NP NP NP Total impurities0.41 1.48 0.80

TABLE 31 Composition 18 Storage Condition Initial 25° C./60% RH 2-8° C.Duration 2 W 2 W Pack (MOC) Glass vial Glass vial Description Clear,colorless solution free from visible particles pH 4.29 4.06 4.22 Assay(Succinylcholine 99.0 96.8 98.2 chloride) Osmolality 308/1540 NP NP(mOsmol/kg) Impurities (% w/w) Succinic acid ND 0.018 NDSuccinylmonocholine 0.616 1.366 0.756 Choline NP NP NP Total impurities0.94 1.98 1.26

TABLE 32 Composition 19 Storage Condition Initial 25° C./60% RH 2-8° C.Duration 2 W 2 W Pack (MOC) Glass vial Glass vial Description Clear,colorless solution free from visible particles pH 4.28 4.15 4.21 Assay(Succinylcholine 99.7 97.2 97.7 chloride) Osmolality (mOsmol/kg)319/1595 NP NP Impurities (% w/w) Succinic acid ND 0.011 NDSuccinylmonocholine 0.321 1.21 0.446 Choline NP NP NP Total impurities0.42 1.59 0.68

TABLE 33 Stability data for Composition A 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.75    3.50    3.61Osmolality (mOsmol/kg) 892*  916*  897*  Assay  98.3  95.7  98.7(Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND    0.13    0.007 Succinylmonocholine    0.09    2.09     0.624 Limit of Choline   0.03    1.54    0.31 Total impurities    0.27    4.41    1.11*reported value is after 1:5 dilution with water.

TABLE 34 Stability data for Composition B 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.72    3.36    3.56Osmolality (mOsmol/kg) 706*  750*  770*  Assay  97.8  95.3  98.3(Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND    0.17   0.01 Succinylmonocholine    0.10    2.61     0.717 Limit of Choline   0.03    1.52    0.34 Total impurities    0.28    4.64    1.27

TABLE 35 Stability data for Composition C 25° C./40% RH 2-8° C. TestInitial 3M 9M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.73    3.39 NA Osmolality(mOsmol/kg) 590*  599*  NA Assay  97.1  94.1 NA (Succinylcholinechloride) Impurities (% w/w) Succinic Acid ND    0.19 0.018Succinylmonocholine    0.07    2.81 1.022 Limit of Choline    0.02   1.70 0.50 Total impurities    0.25    4.96 1.71 PFS: Prefilledsyringe

TABLE 36 Stability data for Composition D 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.65 3.35    3.60 Osmolality(mOsmol/kg) 444*  3275 488*  Assay  98.1 94.5  97.0 (Succinylcholinechloride) Impurities (% w/w) Succinic Acid ND 0.21     0.013Succinylmonocholine    0.09 3.19     0.877 Limit of Choline    0.02 1.91   0.39 Total impurities    0.27 5.57    1.46

TABLE 37 Stability data for Composition F 25° C./40% RH 2-8° C. TestInitial 2M 3M Pack PFS (COC) Glass Vial Description Clear, colourlesssolution free from visible particles pH 3.81 3.41 3.60 Osmolality(mOsmol/kg) 902 902 895 Assay 96.7 94.1 95.7 (Succinylcholine chloride)Impurities (% w/w) Succinic Acid ND 0.11 0.01 Succinylmonocholine 0.1952.43 0.59 Limit of Choline 0.07 1.33 0.26 Total impurities 0.27 4.060.97

TABLE 38 Stability data for Composition G 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH 3.65 3.30 3.56 Osmolality(mOsmol/kg) 2103 2133 1954 Assay 96.7 92.0 98.7 (Succinylcholinechloride) Impurities (% w/w) Succinic Acid ND 0.22 0.01Succinylmonocholine 0.28 3.23 0.85 Limit of Choline 0.08 2.07 0.42 Totalimpurities 0.57 5.73 1.64

TABLE 39 Stability data for Composition H 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.73    3.35    3.53Osmolality (mOsmol/kg) 964*  929*  944*  Assay  98.7  95.2  98.6(Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND    0.14    0.009 Succinylmonocholine     0.092     2.590     0.692 Limit ofCholine ND    1.50    0.29 Total impurities    0.16    4.63    1.08

TABLE 40 Stability data for Composition I 25° C./40% RH 2-8° C. TestInitial 3M 6M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH 3.63 3.28 3.56 Osmolality(mOsmol/kg) 276 286 284 Assay 97.9 90.5 98.6 (Succinylcholine chloride)Impurities (% w/w) Succinic Acid ND 0.30 0.02 Succinylmonocholine 0.334.02 1.04 Limit of Choline 0.11 2.48 0.53 Total impurities 0.64 6.871.92

TABLE 41 Stability data for Composition J 25° C./40% RH 2-8° C. TestInitial 1M 1M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.55    3.42    3.57Osmolality (mOsmol/kg) 485*  495*  494*  Assay  99.8  97.3  99.3(Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND     0.029    0.009 Succinylmonocholine     0.178     1.164     0.285 Limit ofCholine    0.06    0.61    0.02 Total impurities    0.35    1.91    1.41

TABLE 42 Stability data for Composition K 25° C./40% RH 2-8° C. TestInitial 2M 2M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH    3.69    3.37    3.59Osmolality (mOsmol/kg) 536*  537*  542*  Assay  99.1  95.9 97 (Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND    0.01    0.001 Succinylmonocholine     0.124     1.969     0.366 Limit ofCholine    0.06    1.17    0.19 Total impurities    0.29    3.31    0.59

TABLE 43 Stability data for Composition L 25° C./40% RH 2-8° C. TestInitial 1M 1M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH     3.69     3.51     3.59Osmolality (mOsmol/kg) 1011*  1022*  1013*  Assay (Succinylcholine 100.0   96.9   98.3 chloride) Impurities (% w/w) Succinic Acid ND ND NDSuccinylmonocholine      0.103      0.891     0.13 Limit of Choline    0.09     0.48     0.15 Total impurities     0.30     1.44     0.39

TABLE 44 Stability data for Composition M 25° C./40% RH 2-8° C. TestInitial 1M 1M Pack PFS (COC) PFS (COC) Description Clear, colourlesssolution free from visible particles pH   3.70    3.42    3.56Osmolality (mOsmol/kg) 587*   602*  594*  Assay 99.7  96.8  98.8(Succinylcholine chloride) Impurities (% w/w) Succinic Acid ND ND NDSuccinylmonocholine    0.143     1.121     0.372 Limit of Choline   0.14   0.51    0.13 Total impurities   0.37    1.68    0.52

Compositions A to M were found to be stable at 25° C./40% RH and 2-8° C.for at least 30 days. Compositions A-D, F-H & J (containing aliphaticpolyols as stabilizing agents) were found to be physically andchemically stable for at least 30 days at 25° C./40% RH and 2-8° C.Composition K (containing ethanol as stabilizing agent) was also foundto be physically and chemically stable for at least 30 days at 25°C./40% RH and 2-8° C.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that it can be performed within awide equivalent range of parameters without affecting the scope of theinvention or any embodiment thereof. All publications, patentapplications and patents disclosed herein are incorporated by referencein their entirety.

1. An injectable pharmaceutical composition comprising; (i)therapeutically effective amount of succinylcholine chloride; (ii) oneor more stabilizing agents; (iii) one or more pharmaceuticallyacceptable solvents, wherein the composition is stable at roomtemperature for at least 30 days, wherein water is at least one of thepharmaceutically acceptable solvents, and wherein the stabilizing agentsare selected from the group consisting of aliphatic polyols; lower alkylalcohols; amino acids having at least one additional amino, carboxyl orhydroxyl group; amino alcohols; and aliphatic dicarboxylic acids havingat least one hydroxyl or amino group, or α-β unsaturation.
 2. Thecomposition of claim 1, wherein the composition is free of tonicitycontributing agent.
 3. The composition of claim 1, wherein thecomposition is disposed in a pre-filled syringe or vial.
 4. Thecomposition of claim 1, wherein succinylcholine chloride is present atconcentration of about 5 mg/mL to about 60 mg/mL.
 5. The composition ofclaim 1, wherein the stabilizing agent is selected from propyleneglycol, polyethylene glycol, glycerol, cyclodextrin, cyclodextrinderivatives, ethanol, glutamic acid, aspartic acid, arginine, lysine,meglumine, diethanolamine, tromethamine, maleic acid, tartaric acid, andmixtures thereof.
 6. The composition of claim 1, wherein the compositionhas total impurities of less than about 6.0% (w/w) as measured by HPLC,when stored at 25° C./40% RH for up to 90 days.
 7. The composition ofclaim 1, wherein the composition has succinic acid impurity of less thanabout 0.5% (w/w) as measured by HPLC, when stored at 25° C./40% RH forup to 90 days.
 8. The composition of claim 1, wherein the compositionhas succinylmonocholine impurity of less than about 5.0% (w/w) asmeasured by HPLC, when stored at 25° C./40% RH for up to 90 days.
 9. Thecomposition of claim 1, wherein the composition has choline impurity ofless than about 3.0% (w/w) as measured by HPLC, when stored at 25°C./40% RH for up to 90 days.
 10. The composition of claim 1, wherein thecomposition has a pH in the range of from about 3 to about
 5. 11. Thepharmaceutical composition according to claim 3, wherein the pre-filledsyringe is made up of a polymeric materials selected from the groupconsisting of polysulfone, polycarbonate, polypropylene, polyethylene,ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers,polyester, poly (1,1,2,2 tetrafluoroethylene), Nylon, polyoxymethylene,polymethylpentene, polyvinylidene chloride, ethylvinylacetate, cyclicolefin polymer, cyclic olefin copolymer, crystal zenith, and mixturesthereof.
 12. The pharmaceutical composition of claim 1, wherein thecomposition is sterilized using a technique selected from the groupconsisting of filtration through aseptic filtration-filling-sealingprocess, terminal sterilization, incorporation of sterilizing agents,irradiation, and heating.
 13. A kit comprising the composition of claim1, wherein the kit further comprises an injection device foradministration of the composition to a subject in need of suchpharmaceutical composition.
 14. The kit of claim 13, wherein theinjection device comprises a needle and prefilled syringe or syringecartridge with the composition disposed therein.
 15. The composition ofclaim 1, wherein the aliphatic polyols and/or lower alkyl alcohols arepresent at a concentration of less than about 300 mg/mL.
 16. Thecomposition of claim 15, wherein the concentration is from about 20mg/mL to about 300 mg/mL.
 17. The composition of claim 1, wherein theamino acids having at least one additional amino, carboxyl or hydroxylgroup; amino alcohols; and/or aliphatic dicarboxylic acids having atleast one hydroxyl or amino group, or α-β unsaturation are present at aconcentration of less than about 2 mg/mL.
 18. The composition of claim17, wherein the concentration is from about 0.1 mg/mL to about 2 mg/mL.19. An injectable pharmaceutical composition comprising; (i)succinylcholine chloride at a concentration of about 20 mg/mL, (ii)propylene glycol, (iii) purified water, wherein the composition is freeof sodium chloride, wherein the composition is disposed in a pre-filledsyringe and is stable at room temperature for at least 30 days.
 20. Thecomposition of claim 1, wherein succinylcholine chloride is present at aconcentration of 20 mg/mL.
 21. A method of providing succinylcholine asan adjunct to general anesthesia, to facilitate tracheal intubation, andto provide skeletal muscle relaxation during surgery or mechanicalventilation to a human subject in need thereof comprising administrationof the subject the injectable pharmaceutical compositions of claim 1.